Early post-operative interleukin-6 and tumor necrosis factor-α levels after single-port laparoscopic varicocelectomy in children

Purpose  

Laparoendoscopic single-site surgery has recently been described in children and regarded as an improved technology leading to less pain and better cosmetic outcome. Compared to the traditional three-port method, it is not known if the single-port method is less invasive. The aim of this study was thus to investigate the post-operative acute inflammatory response in order to evaluate surgical stress in the two surgical approaches in children.     

Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways

Tumor relapse and metastasis remain major obstacles for improving overall cancer survival, which may be due at least in part to the existence of cancer stem cells (CSCs). CSCs are characterized by tumorigenic properties and the ability to self-renew, form differentiated progeny, and develop resistance to therapy. CSCs use many of the same signaling pathways that are found in normal stem cells, such as Wnt, Notch, and Hedgehog (Hh). The origin of CSCs is not fully understood, but data suggest that they originate from normal stem or progenitor cells, or possibly other cancer cells. Therapeutic targeting of both CSCs and bulk tumor populations may provide a strategy to suppress tumor regrowth. Development of agents that target critical steps in the Wnt, Notch, and Hh pathways will be complicated by signaling cross-talk. The role that embryonic signaling pathways play in the function of CSCs, the development of new anti-CSC therapeutic agents, and the complexity of potential CSC signaling cross-talk are described in this Review.     

The association of breast density with breast cancer mortality in African American and white women screened in community practice

The effect of breast density on survival outcomes for American women who participate in screening remains unknown. We studied the role of breast density on both breast cancer and other cause of mortality in screened women. Data for women with breast cancer, identified from the community-based Carolina Mammography Registry, were linked with the North Carolina cancer registry and NC death tapes for this study. Cause-specific Cox proportional hazards models were developed to analyze the effect of several covariates on breast cancer mortality—namely, age, race (African American/White), cancer stage at diagnosis (in situ, local, regional, and distant), and breast density (BI-RADS ^® 1–4). Two stratified Cox models were considered controlling for (1) age and race, and (2) age and cancer stage, respectively, to further study the effect of density. The cumulative incidence function with confidence interval approximation was used to quantify mortality probabilities over time. For this study, 22,597 screened women were identified as having breast cancer. The non-stratified and stratified Cox models showed no significant statistical difference in mortality between dense tissue and fatty tissue, while controlling for other covariate effects (p value = 0.1242, 0.0717, and 0.0619 for the non-stratified, race-stratified, and cancer stage–stratified models, respectively). The cumulative mortality probability estimates showed that women with dense breast tissues did not have significantly different breast cancer mortality than women with fatty breast tissue, regardless of age (e.g., 10-year confidence interval of mortality probabilities for whites aged 60–69 white: 0.056–0.090 vs. 0.054–0.083). Aging, African American race, and advanced cancer stage were found to be significant risk factors for breast cancer mortality (hazard ratio >1.0). After controlling for cancer incidence, there was not a significant association between mammographic breast density and mortality, adjusting for the effects of age, race, and cancer stage.     

Hemicholinium-3 mustard reveals two populations of cycling choline cotransporters in Limulus

Cholinergic neurons have both a low-affinity and a high-affinity choline transport process. The high-affinity choline transport is sodium dependent and thus it can be referred to as choline cotransport. Choline cotransport has been shown to be up-regulated by neuronal activity. Protein kinase C has also been shown to regulate choline cotransport. Both forms of regulation appear to modulate transport by altering the numbers of choline cotransporters in the nerve terminal membrane. The present study centers on choline cotransporter trafficking in Limulus brain hemi-slice preparations. The competitive, reversible, non-permeant ligand, [3H]hemicholinium-3, was used in binding studies to estimate the relative number of choline cotransporters in plasma membranes. The hemicholinium-3 mustard derivative has been shown to be an irreversible, highly selective, non-permeant ligand for the choline cotransporter, and was also used. Hemicholinium-3 mustard binding to the choline cotransporter blocked [3H]choline transport and [3H]hemicholinium-3 binding. Antecedent elevated potassium exposure of cholinergic tissues has been shown to up-regulate choline transport by the recruitment of additional choline cotransporters to surface membranes. This treatment was also effective in the recruitment of cotransporters following maximal inhibition by hemicholinium-3 mustard of brain hemi-slices. Long-term washout of hemicholinium-3 mustard in hemi-slices resulted in a time-dependent restoration of choline cotransport. Full recovery occurred within 2h. In uninhibited slice preparations, both staurosporine and chelerythrine, protein kinase C inhibitors, stimulated choline uptake. However, within a 1-h washout recovery of uptake following hemicholinium-3 mustard inhibition, the staurosporine responsive but not chelerythrine responsive transport had returned. On the basis of these findings, we hypothesize the existence of two distinct populations of cycling choline cotransporters, which includes inactive or "silent" transporters.     

Synthesis and nicotinic acetylcholine receptor in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogues of 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine

Herein, we report the synthesis and nicotinic acetylcholine receptor (nAChR) in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidines 5b-g, analogues of 3'-(4-nitrophenyl) compound 5a. All compounds had high affinity for α4β2-nAChR and low affinity for α7-nAChR. Initial electrophysiological studies showed that all analogues were antagonists at α4β2-, α3β4-, and α7-nAChRs. The 4-carbamoylphenyl analogue 5g was highly selective for α4β2-nAChR over α3β4- and α7-nAChRs. All the analogues were antagonists of nicotine-induced antinociception in the tail-flick test. Molecular modeling docking studies using the agonist-bound form of the X-ray crystal structure of the acetylcholine binding protein suggested several different binding modes for epibatidine, varenicline, and 5a-g. In particular, a unique binding mode for 5g was suggested by these docking simulations. The high binding affinity, in vitro efficacy, and selectivity of 5g for α4β2-nAChR combined with its nAChR functional antagonist properties suggest that 5g will be a valuable pharmacological tool for studying the nAChR and may have potential as a pharmacotherapy for addiction and other central nervous system disorders.